title: Biochemical and structural insights into intramembrane metalloprotease mechanisms.
abstract: Intramembrane metalloproteases are nearly ubiquitous in living organisms and they function in diverse processes ranging from cholesterol homeostasis and the unfolded protein response in humans to sporulation, stress responses, and virulence of bacteria. Understanding how these enzymes function in membranes is a challenge of fundamental interest with potential applications if modulators can be devised. Progress is described toward a mechanistic understanding, based primarily on molecular genetic and biochemical studies of human S2P and bacterial SpoIVFB and RseP, and on the structure of the membrane domain of an archaeal enzyme. Conserved features of the enzymes appear to include transmembrane helices and loops around the active site zinc ion, which may be near the membrane surface. Extramembrane domains such as PDZ (PSD-95, DLG, ZO-1) or CBS (cystathionine-β-synthase) domains govern substrate access to the active site, but several different mechanisms of access and cleavage site selection can be envisioned, which might differ depending on the substrate and the enzyme. More work is needed to distinguish between these mechanisms, both for enzymes that have been relatively well-studied, and for enzymes lacking PDZ and CBS domains, which have not been studied. This article is part of a Special Issue entitled: Intramembrane Proteases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: kroos@msu.edu.
authors.forename: Lee
authors.initials: L
authors.lastname: Kroos
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Akiyama
mesh_terms: D017360:Arabidopsis / Q000737:chemistry / Q000201:enzymology; D001105:Archaea / Q000737:chemistry / Q000201:enzymology; D019843:Archaeal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D019843:Archaeal Proteins; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D008565:Membrane Proteins; D010450:Endopeptidases; C440001:RseP protein, E coli; D008666:Metalloendopeptidases; C071442:spoIVFB protein, Bacillus subtilis; C120654:MBTPS2 protein, human
keywords: (PSD-95, DLG, ZO-1); (cystathionine-β-synthase); CBS; CBS domain; GFP; IMMP(s); IP(s); Intramembrane metalloprotease; OMP(s); PDZ; PDZ domain; RNA polymerase; RNAP; RseP; S1P; S2P; SCAP; SREBP(s); SREBP-cleavage-activating protein; SpoIVFB; TMS(s); green fluorescent protein; intramembrane metalloprotease(s); intramembrane protease(s); outer membrane protein(s); site-1 protease; site-2 protease; sterol-regulatory element-binding protein(s); transmembrane segment(s)